Evolutionary Conserved Regulation of HIF-1β by NF-κB
Open accessAbstract
Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-α subunit quantities and their associated activity are regulated in a post-translational manner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively. However, alternative modes of HIF-α regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-κB regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-κB directly regulates HIF-1β mRNA and protein. In addition, we found that NF-κB-mediated changes in HIF-1β result in modulation of HIF-2α protein. HIF-1β overexpression can rescue HIF-2α protein levels following NF-κB depletion. Significantly, NF-κB regulates HIF-1β (tango) and HIF-α (sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conserved mode of regulation. These results reveal a novel mechanism of HIF regulation, with impact in the development of novel therapeutic strategies for HIF-related pathologies including ageing, ischemia, and cancer.
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NF-κB regulates the hypoxic response by stimulating HIF-1α and HIF-1β transcription and by IKK-dependent stabilization of HIF-2α.
“Additionally, numerous studies have shown that NF-κB regulates the hypoxic response by stimulating the transcription of HIF-1α and HIF-1β, and by inducing IKK-dependent stabilization of HIF-2α [15–17].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [17]
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The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation
Acuña-Pilarte, K., & Koh, M. Y. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.06.005 · Cited by 41 · see citing works
- Authors
- van Uden, P., Kenneth, N. S., Webster, R., Müller, H. A., Mudie, S., & Rocha, S.
- Affiliations
- University of Dundee (GB)
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-01-27
- Volume
- 7
- Issue
- 1
- Pages
- e1001285
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3029248
- OpenAlex
- W2064892294
- Cited by
- 163
- References
- 55
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 12 · 2023: 11 · 2022: 12 · 2021: 15 · 2020: 12 · 2019: 12 · 2018: 6 · 2017: 13 · 2016: 7 · 2015: 12 · 2014: 8 · 2013: 15 · 2012: 9
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- University of Dundee
- Wellcome Trust (083524)
- Research Councils UK
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- ARNT, NF-κB, hypoxia-inducible factor, HIF-2α, transcriptional regulation, evolutionary conservation, Drosophila, hypoxia, translational regulation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Hypoxia, Drosophila melanogaster, Fibroblasts, Gene Expression Regulation, HeLa Cells, Humans, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Drosophila Proteins, RNA, Small Interfering, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, Gene Regulatory Networks, HEK293 Cells
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